Compulsive cocaine (COC) abuse in humans is associated with an intermediate withdrawal phase (3-10 days after withdrawal), which may be related to a high rate of recidivism. Understanding neurobiological alterations characterizing this phase may be critical in formulating a rational treatment/prevention of repeated COC abuse. We hypothesize that withdrawal from chronic COC exposure is associated with time-dependent alterations in auto-inhibition of single dopamine (DA) neurons, effects analogous to those observed with amphetamine withdrawal. Establishing that these changes occur following continuous (vs. intermittent) COC will help in elucidating possible mechanisms underlying the COC recidivism. We will determine responses of nigrostriatal and mesoaccumbens DA neurons to apomorphine (mixed D1 and D2 agonist) and B-HT 920 (selective D2 agonist) during withdrawal from continuous or intermittent COC exposures. The single-unit data will be supplemented by determining the locomotor inhibition by low doses of agonists (a behavioral index of autoreceptor function), which should parallel the single-unit data. As the nigrostriatal and mesoaccumbens DA pathways differ in their acute and chronic responses to various DA agents, the projection area of each recorded neuron will be identified. In vivo, this task will be achieved by antidromic stimulation from the terminal regions. For in vitro recordings, a novel recording technique utilizing a priori labelling of DA cell bodies will be developed during the first year of this project. By injecting rhodamine-labelled fluorescent microspheres (a fluorescent retrograde tracer) into the terminal regions, DA neurons projecting to different terminal regions will be readily identified without a significant decrement in viability. Following its development, the in vitro technique will be used to examine chronic COC-induced changes. Data from these studies are expected to facilitate a rational approach to understanding and treating withdrawal from compulsive COC abuse in humans.